Data | SynGAP Server

c.dna	Variant	SGM Consensus	Domain	ClinVar			gnomAD			ESM1b		AlphaMissense			REVEL		FoldX			Rosetta		Foldetta		PremPS		PROVEAN		PolyPhen-2 HumDiv		PolyPhen-2 HumVar		FATHMM		SIFT				PAM		Physical		SASA		Normalized B-factor backbone		Normalized B-factor sidechain		SynGAP Structural Annotation									DOI
c.dna	Variant	SGM Consensus	Domain	Clinical Status	Review	Subm.	ID	Allele count	Allele freq.	LLR score	Prediction	Pathogenicity	Class	Optimized	Score	Prediction	Average ΔΔG	Prediction	StdDev	ΔΔG	Prediction	ΔΔG	Prediction	ΔΔG	Prediction	Score	Prediction	pph2_prob	Prediction	pph2_prob	Prediction	Nervous System Score	Prediction	Prediction	Status	Conservation	Sequences	PAM250	PAM120	Hydropathy Δ	MW Δ	Average	Δ	Δ	StdDev	Δ	StdDev	Secondary	Tertiary bonds	Inside out	GAP-Ras interface	At membrane	No effect	MD Alert	Verdict	Description	DOI
c.2729G>C	G910A	Likely Benign		Uncertain		1	6-33443281-G-C	1	6.20e-7	-3.587	Likely Benign	0.361	Ambiguous	Likely Benign	0.209	Likely Benign										-1.43	Neutral	0.999	Probably Damaging	0.999	Probably Damaging	2.78	Benign	0.10	Tolerated	3.77	5	1	0	2.2	14.03													MD Alert	Verdict	Description
c.3923G>A	R1308H			Uncertain		1	6-33451797-G-A	3	1.86e-6	-3.586	Likely Benign	0.201	Likely Benign	Likely Benign	0.319	Likely Benign										-3.12	Deleterious	0.998	Probably Damaging	0.991	Probably Damaging	2.33	Pathogenic	0.00	Affected	3.77	5	2	0	1.3	-19.05
c.3567G>C	E1189D	Likely Benign	Coiled-coil	Likely Benign		1	6-33444602-G-C	3	1.86e-6	-3.582	Likely Benign	0.461	Ambiguous	Likely Benign	0.359	Likely Benign										-1.42	Neutral	0.992	Probably Damaging	0.989	Probably Damaging	5.30	Benign	0.25	Tolerated	3.82	4	3	2	0.0	-14.03
c.2350G>A	A784T	Likely Benign		Benign		1				-3.579	Likely Benign	0.089	Likely Benign	Likely Benign	0.046	Likely Benign										1.23	Neutral	0.001	Benign	0.006	Benign	2.92	Benign	1.00	Tolerated	3.64	6	1	0	-2.5	30.03
c.1485A>C	E495D (3D Viewer)	Likely Pathogenic	GAP	Conflicting		2				-3.574	Likely Benign	0.958	Likely Pathogenic	Likely Pathogenic	0.566	Likely Pathogenic	1.39	Ambiguous	0.1	1.03	Ambiguous	1.21	Ambiguous	0.98	Ambiguous	-2.52	Deleterious	0.998	Probably Damaging	0.989	Probably Damaging	-1.41	Pathogenic	0.17	Tolerated	3.37	35	3	2	0.0	-14.03	220.6	38.8	0.0	0.0	0.1	0.1		X		X				Uncertain	Glu495 is located in the α-helix (res. Leu489-Glu519), and its carboxylate group forms salt bridges with the neighboring Lys492 and with Arg596 on an opposing α-helix (res. Glu582-Met603) in the WT simulations. In the variant simulations, the acidic carboxylate side chain of Asp495 can also form salt bridges with both Lys492 and Arg596. However, the shorter side chain of aspartate tends to favor forming a salt bridge with the nearby Arg499 on the same α-helix instead. Asp495 might not maintain the salt bridge with Arg596 on the opposing α-helix as efficiently as Glu495 in the WT, potentially weakening the tertiary structure. Regardless, the potential negative effect is likely to be minor, with no deleterious effects observed on the protein structure during the simulations. However, due to its location at the GAP-Ras interface, the effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations.
c.745G>A	A249T (3D Viewer)	Likely Benign	PH	Uncertain		1				-3.564	Likely Benign	0.805	Likely Pathogenic	Ambiguous	0.487	Likely Benign	1.50	Ambiguous	0.6	1.39	Ambiguous	1.45	Ambiguous	0.30	Likely Benign	-0.96	Neutral	0.990	Probably Damaging	0.815	Possibly Damaging	5.65	Benign	0.40	Tolerated	3.39	15	1	0	-2.5	30.03	214.5	-43.3	0.0	0.0	0.5	0.2						X		Potentially Benign	The methyl group of Ala249, located on the surface of an α helix (res. Ala236-Val250) facing an anti-parallel β sheet strand (res. Ile205-Val209), packs against nearby hydrophobic residues such as Leu200, Leu246, and Val250. In the variant simulations, the hydroxyl group of Thr249, which is not suitable for hydrophobic packing, forms a stable hydrogen bond with the backbone carbonyl of Asn245 in the same helix. Although this interaction could theoretically weaken the structural integrity of the α helix, this destabilizing effect is not observed in the variant simulations.
c.311G>T	R104L	Likely Benign		Benign		1	6-33432176-G-T	1	6.20e-7	-3.563	Likely Benign	0.578	Likely Pathogenic	Likely Benign	0.170	Likely Benign										-1.38	Neutral	0.001	Benign	0.002	Benign	4.05	Benign	0.00	Affected	4.32	1	-2	-3	8.3	-43.03
c.2349G>A	M783I	Likely Benign		Benign		1	6-33442901-G-A	6	3.72e-6	-3.560	Likely Benign	0.418	Ambiguous	Likely Benign	0.042	Likely Benign										-0.54	Neutral	0.004	Benign	0.006	Benign	2.87	Benign	0.22	Tolerated	3.64	6	1	2	2.6	-18.03
c.44C>T	A15V	Likely Benign		Uncertain		1	6-33420308-C-T	1	6.49e-7	-3.560	Likely Benign	0.161	Likely Benign	Likely Benign	0.105	Likely Benign										0.20	Neutral	0.602	Possibly Damaging	0.015	Benign	4.19	Benign	0.00	Affected	4.32	1	0	0	2.4	28.05
c.2743G>A	G915S	Likely Benign		Benign		1	6-33443295-G-A	9	5.58e-6	-3.557	Likely Benign	0.083	Likely Benign	Likely Benign	0.050	Likely Benign										-0.88	Neutral	0.801	Possibly Damaging	0.201	Benign	2.73	Benign	0.31	Tolerated	3.77	5	1	0	-0.4	30.03
c.59C>G	P20R	Likely Benign		Uncertain		1				-3.548	Likely Benign	0.434	Ambiguous	Likely Benign	0.146	Likely Benign										-0.15	Neutral	0.972	Probably Damaging	0.804	Possibly Damaging	4.33	Benign	0.00	Affected	4.32	1	0	-2	-2.9	59.07
c.3304G>A	A1102T	Likely Benign		Uncertain		1	6-33443856-G-A	11	7.17e-6	-3.540	Likely Benign	0.070	Likely Benign	Likely Benign	0.044	Likely Benign										-0.30	Neutral	0.001	Benign	0.001	Benign	2.32	Pathogenic	0.95	Tolerated	3.77	5	1	0	-2.5	30.03
c.1108G>A	G370S (3D Viewer)	Likely Benign	C2	Uncertain		1	6-33438013-G-A	15	9.31e-6	-3.533	Likely Benign	0.081	Likely Benign	Likely Benign	0.282	Likely Benign	2.83	Destabilizing	2.0	1.05	Ambiguous	1.94	Ambiguous	-0.02	Likely Benign	0.47	Neutral	0.000	Benign	0.000	Benign	1.33	Pathogenic	0.77	Tolerated	3.42	19	1	0	-0.4	30.03	196.6	-49.6	0.9	2.2	-0.1	0.4								Uncertain	Gly370 is located in the Gly-rich Ω loop (res. Pro364- Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because, the Ω loop is assumed to be directly interacting with the membrane, it is only seen to move arbitrarily throughout the WT solvent simulations. The Ω loop is potentially playing a crucial loop in the SynGAP-membrane complex association, stability and dynamics, regardless, this aspect cannot be addressed through the solvent simulations only. The Ω-loops are known to have a major role in protein functions that requires flexibility and thus, they are rich in glycines, prolines and to a lesser extent, hydrophilic residues to ensure maximum flexibility. Thus, Ser370 in the variant is potentially tolerated in the Ω loop. However, since the effect on the Gly-rich Ω loop dynamics can only be well-studied through the SynGAP-membrane complex, no definite conclusions can be withdrawn.
c.2860C>T	P954S	Likely Benign		Likely Benign		1	6-33443412-C-T	1	6.20e-7	-3.525	Likely Benign	0.062	Likely Benign	Likely Benign	0.143	Likely Benign										-0.25	Neutral	0.954	Possibly Damaging	0.812	Possibly Damaging	2.87	Benign	1.00	Tolerated	3.77	5	1	-1	0.8	-10.04
c.3949G>A	G1317S	Likely Benign		Conflicting		3	6-33451823-G-A	1	6.26e-7	-3.522	Likely Benign	0.145	Likely Benign	Likely Benign	0.092	Likely Benign										-2.45	Neutral	0.127	Benign	0.045	Benign	4.08	Benign	0.00	Affected	3.77	5	1	0	-0.4	30.03
c.2900G>T	R967L	Likely Benign		Uncertain		1	6-33443452-G-T	1	6.20e-7	-3.496	Likely Benign	0.164	Likely Benign	Likely Benign	0.123	Likely Benign										-0.99	Neutral	0.959	Probably Damaging	0.586	Possibly Damaging	4.15	Benign	0.75	Tolerated	4.32	2	-2	-3	8.3	-43.03
c.4013G>A	R1338Q	Likely Benign		Conflicting		3	6-33451887-G-A	12	8.40e-6	-3.494	Likely Benign	0.317	Likely Benign	Likely Benign	0.076	Likely Benign										-1.87	Neutral	0.896	Possibly Damaging	0.194	Benign	3.81	Benign	0.02	Affected	3.77	5	1	1	1.0	-28.06
c.3059G>C	R1020P	Likely Pathogenic		Uncertain		1				-3.491	Likely Benign	0.902	Likely Pathogenic	Ambiguous	0.205	Likely Benign										-3.50	Deleterious	0.999	Probably Damaging	0.977	Probably Damaging	2.46	Pathogenic	0.00	Affected			0	-2	2.9	-59.07
c.106C>T	H36Y	Likely Benign		Uncertain		1	6-33423515-C-T	2	1.24e-6	-3.461	Likely Benign	0.139	Likely Benign	Likely Benign	0.023	Likely Benign										-1.03	Neutral	0.219	Benign	0.066	Benign	4.16	Benign	0.00	Affected	4.32	1	0	2	1.9	26.03
c.3119G>T	G1040V	Likely Pathogenic		Uncertain		1	6-33443671-G-T	4	2.48e-6	-3.453	Likely Benign	0.645	Likely Pathogenic	Likely Benign	0.774	Likely Pathogenic										-2.89	Deleterious	0.827	Possibly Damaging	0.456	Possibly Damaging	-0.74	Pathogenic	0.01	Affected	3.77	5	-1	-3	4.6	42.08
c.901G>A	A301T (3D Viewer)	Likely Benign	C2	Uncertain		5	6-33437806-G-A	2	1.24e-6	-3.448	Likely Benign	0.070	Likely Benign	Likely Benign	0.150	Likely Benign	0.36	Likely Benign	0.2	-0.33	Likely Benign	0.02	Likely Benign	0.03	Likely Benign	-0.25	Neutral	0.997	Probably Damaging	0.989	Probably Damaging	4.15	Benign	0.22	Tolerated	4.32	14	1	0	-2.5	30.03	219.8	-42.8	-0.1	0.0	-0.5	0.2								Uncertain	The methyl group of Ala301, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), points outward from the β hairpin loop, and its backbone atoms do not participate in the loop formation in the WT simulations. In the variant simulations, the hydroxyl group of the Thr301 side chain also mostly points outward; however, the guanidinium group of Arg299 is moved away from its central hairpin loop position.β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Due to its location near the membrane surface, the residue swap could also affect the C2 loop dynamics and SynGAP-membrane association. However, this is beyond the scope of the solvent-only simulations to unravel.
c.43G>C	A15P	Likely Benign		Uncertain		1				-3.436	Likely Benign	0.097	Likely Benign	Likely Benign	0.146	Likely Benign										-0.23	Neutral	0.880	Possibly Damaging	0.123	Benign	4.09	Benign	0.00	Affected			1	-1	-3.4	26.04
c.3048C>A	D1016E	Likely Benign		Likely Benign		1	6-33443600-C-A	2	1.24e-6	-3.422	Likely Benign	0.216	Likely Benign	Likely Benign	0.017	Likely Benign										-0.37	Neutral	0.008	Benign	0.028	Benign	2.64	Benign	0.65	Tolerated	3.77	5	2	3	0.0	14.03
c.3529G>A	E1177K	Likely Benign	Coiled-coil	Uncertain		1				-3.413	Likely Benign	0.944	Likely Pathogenic	Ambiguous	0.560	Likely Pathogenic										-1.75	Neutral	0.905	Possibly Damaging	0.637	Possibly Damaging	5.44	Benign	0.11	Tolerated	4.32	2	0	1	-0.4	-0.94
c.233G>T	R78L	Likely Benign		Uncertain		1				-3.389	Likely Benign	0.635	Likely Pathogenic	Likely Benign	0.062	Likely Benign										-1.59	Neutral	0.385	Benign	0.021	Benign	3.84	Benign	0.00	Affected			-3	-2	8.3	-43.03
c.2255C>T	S752L	Likely Benign		Uncertain		2	6-33441720-C-T	6	3.72e-6	-3.386	Likely Benign	0.182	Likely Benign	Likely Benign	0.195	Likely Benign										-2.09	Neutral	0.993	Probably Damaging	0.641	Possibly Damaging	1.51	Pathogenic	0.01	Affected	3.99	5	-3	-2	4.6	26.08
c.2502G>C	M834I	Likely Benign		Uncertain		1				-3.377	Likely Benign	0.291	Likely Benign	Likely Benign	0.055	Likely Benign										-1.21	Neutral	0.026	Benign	0.009	Benign	2.56	Benign	0.00	Affected	4.32	4	1	2	2.6	-18.03
c.2217G>C	E739D	Likely Benign		Uncertain		1				-3.369	Likely Benign	0.062	Likely Benign	Likely Benign	0.097	Likely Benign										-0.49	Neutral	0.002	Benign	0.005	Benign	2.59	Benign	0.00	Affected			3	2	0.0	-14.03
c.3397A>G	I1133V	Likely Benign		Benign		1	6-33443949-A-G	22	1.48e-5	-3.362	Likely Benign	0.067	Likely Benign	Likely Benign	0.180	Likely Benign										0.06	Neutral	0.007	Benign	0.007	Benign	5.47	Benign	0.58	Tolerated	4.32	3	4	3	-0.3	-14.03																10.1016/j.ajhg.2020.11.011
c.2596G>T	V866L	Likely Benign		Uncertain		1	6-33443148-G-T	1	6.20e-7	-3.352	Likely Benign	0.148	Likely Benign	Likely Benign	0.046	Likely Benign										-0.97	Neutral	0.217	Benign	0.229	Benign	2.71	Benign	0.21	Tolerated	3.82	4	2	1	-0.4	14.03
c.4008G>C	E1336D	Likely Benign		Likely Benign		1				-3.344	Likely Benign	0.596	Likely Pathogenic	Likely Benign	0.062	Likely Benign										-1.92	Neutral	0.001	Benign	0.003	Benign	3.30	Benign	0.00	Affected	3.77	5	2	3	0.0	-14.03
c.136C>T	P46S	Likely Benign		Uncertain		1				-3.338	Likely Benign	0.302	Likely Benign	Likely Benign	0.066	Likely Benign										-0.60	Neutral	0.909	Possibly Damaging	0.901	Possibly Damaging	4.15	Benign	0.00	Affected			1	-1	0.8	-10.04
c.2243T>G	L748R	Likely Benign		Conflicting		2	6-33441708-T-G	3	1.86e-6	-3.331	Likely Benign	0.245	Likely Benign	Likely Benign	0.055	Likely Benign										-0.67	Neutral	0.912	Possibly Damaging	0.448	Possibly Damaging	2.73	Benign	0.02	Affected	4.32	2	-3	-2	-8.3	43.03
c.82T>C	S28P	Likely Benign		Uncertain		1				-3.309	Likely Benign	0.051	Likely Benign	Likely Benign	0.047	Likely Benign										1.37	Neutral	0.000	Benign	0.000	Benign	4.53	Benign	0.00	Affected	4.32	1	1	-1	-0.8	10.04
c.127G>A	G43S	Likely Benign		Uncertain		2	6-33423536-G-A	1	6.20e-7	-3.301	Likely Benign	0.078	Likely Benign	Likely Benign	0.057	Likely Benign										-0.30	Neutral	0.162	Benign	0.096	Benign	4.29	Benign	0.00	Affected	4.32	1	1	0	-0.4	30.03
c.2765G>A	R922Q	Likely Benign		Benign		1	6-33443317-G-A	7	4.34e-6	-3.295	Likely Benign	0.189	Likely Benign	Likely Benign	0.085	Likely Benign										-0.27	Neutral	0.992	Probably Damaging	0.736	Possibly Damaging	2.57	Benign	0.20	Tolerated	3.77	5	1	1	1.0	-28.06
c.59C>T	P20L	Likely Benign		Uncertain		3				-3.289	Likely Benign	0.464	Ambiguous	Likely Benign	0.100	Likely Benign										-0.44	Neutral	0.909	Possibly Damaging	0.713	Possibly Damaging	4.27	Benign	0.00	Affected	4.32	1	-3	-3	5.4	16.04
c.3238G>T	A1080S	Likely Benign		Uncertain		1	6-33443790-G-T	1	6.26e-7	-3.277	Likely Benign	0.108	Likely Benign	Likely Benign	0.103	Likely Benign										0.01	Neutral	0.702	Possibly Damaging	0.346	Benign	4.16	Benign	0.08	Tolerated	3.77	5	1	1	-2.6	16.00
c.3053C>T	T1018I			Uncertain		1	6-33443605-C-T	4	2.48e-6	-3.264	Likely Benign	0.524	Ambiguous	Likely Benign	0.076	Likely Benign										-2.55	Deleterious	0.586	Possibly Damaging	0.304	Benign	2.24	Pathogenic	0.01	Affected	3.77	5	-1	0	5.2	12.05
c.3502A>G	I1168V	Likely Benign		Uncertain		1				-3.263	Likely Benign	0.524	Ambiguous	Likely Benign	0.363	Likely Benign										-0.14	Neutral	0.876	Possibly Damaging	0.643	Possibly Damaging	5.47	Benign	0.84	Tolerated	3.88	3	4	3	-0.3	-14.03
c.3134C>G	A1045G	Likely Benign		Benign/Likely benign		7	6-33443686-C-G	1407	8.72e-4	-3.246	Likely Benign	0.075	Likely Benign	Likely Benign	0.024	Likely Benign										-1.21	Neutral	0.224	Benign	0.066	Benign	2.64	Benign	0.33	Tolerated	3.77	5	1	0	-2.2	-14.03																10.1016/j.ajhg.2020.11.011
c.3136C>G	P1046A	Likely Benign		Uncertain		1	6-33443688-C-G	1	6.20e-7	-3.246	Likely Benign	0.048	Likely Benign	Likely Benign	0.041	Likely Benign										-1.67	Neutral	0.001	Benign	0.008	Benign	2.39	Pathogenic	0.29	Tolerated	3.77	5	-1	1	3.4	-26.04
c.291G>T	E97D	Likely Benign		Uncertain		3	6-33425899-G-T			-3.239	Likely Benign	0.077	Likely Benign	Likely Benign	0.081	Likely Benign										-0.49	Neutral	0.880	Possibly Damaging	0.636	Possibly Damaging	4.12	Benign	0.00	Affected	4.32	1	3	2	0.0	-14.03
c.272A>G	E91G	Likely Benign		Likely Benign		1				-3.226	Likely Benign	0.783	Likely Pathogenic	Likely Benign	0.110	Likely Benign										-2.18	Neutral	0.947	Possibly Damaging	0.727	Possibly Damaging	3.86	Benign	0.00	Affected	4.32	1	0	-2	3.1	-72.06
c.4021G>A	A1341T	Likely Benign		Conflicting		3	6-33451895-G-A	45	3.44e-5	-3.224	Likely Benign	0.081	Likely Benign	Likely Benign	0.099	Likely Benign										-0.58	Neutral	0.000	Benign	0.000	Benign	4.09	Benign	0.03	Affected	3.77	5	1	0	-2.5	30.03
c.3023A>G	D1008G			Uncertain		1	6-33443575-A-G	1	6.20e-7	-3.213	Likely Benign	0.742	Likely Pathogenic	Likely Benign	0.203	Likely Benign										-2.84	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	2.65	Benign	0.01	Affected	3.77	5	-1	1	3.1	-58.04
c.280C>T	P94S	Likely Benign		Benign		1	6-33425888-C-T	5	3.10e-6	-3.151	Likely Benign	0.084	Likely Benign	Likely Benign	0.093	Likely Benign										-2.36	Neutral	0.092	Benign	0.008	Benign	4.13	Benign	0.00	Affected	4.32	1	1	-1	0.8	-10.04
c.2291A>G	N764S	Likely Benign		Benign		1				-3.149	Likely Benign	0.159	Likely Benign	Likely Benign	0.058	Likely Benign										-0.84	Neutral	0.992	Probably Damaging	0.846	Possibly Damaging	2.65	Benign	0.61	Tolerated	3.64	6	1	1	2.7	-27.03
c.2216A>T	E739V	Likely Benign		Uncertain		1				-3.136	Likely Benign	0.274	Likely Benign	Likely Benign	0.085	Likely Benign										-1.86	Neutral	0.891	Possibly Damaging	0.575	Possibly Damaging	2.47	Pathogenic	0.00	Affected	4.32	2	-2	-2	7.7	-29.98
c.3026A>C	E1009A	Likely Pathogenic		Uncertain		1				-3.118	Likely Benign	0.679	Likely Pathogenic	Likely Benign	0.109	Likely Benign										-3.06	Deleterious	0.980	Probably Damaging	0.630	Possibly Damaging	2.39	Pathogenic	0.01	Affected	3.77	5	0	-1	5.3	-58.04
c.3002T>C	L1001P	Likely Benign		Uncertain		1				-3.071	Likely Benign	0.209	Likely Benign	Likely Benign	0.113	Likely Benign										-1.02	Neutral	0.966	Probably Damaging	0.690	Possibly Damaging	2.65	Benign	0.00	Affected	4.32	4	-3	-3	-5.4	-16.04
c.2246G>A	R749Q	Likely Benign		Likely Benign		1	6-33441711-G-A	4	2.48e-6	-3.069	Likely Benign	0.212	Likely Benign	Likely Benign	0.152	Likely Benign										-1.00	Neutral	0.999	Probably Damaging	0.994	Probably Damaging	2.64	Benign	0.03	Affected	4.32	2	1	1	1.0	-28.06
c.2900G>A	R967Q	Likely Benign		Benign/Likely benign		2	6-33443452-G-A	31	1.92e-5	-3.057	Likely Benign	0.080	Likely Benign	Likely Benign	0.104	Likely Benign										-0.01	Neutral	0.994	Probably Damaging	0.626	Possibly Damaging	4.21	Benign	0.36	Tolerated	4.32	2	1	1	1.0	-28.06
c.2493G>C	E831D	Likely Benign		Uncertain		1	6-33443045-G-C	1	6.19e-7	-3.055	Likely Benign	0.063	Likely Benign	Likely Benign	0.073	Likely Benign										1.23	Neutral	0.002	Benign	0.002	Benign	2.64	Benign	0.77	Tolerated	3.77	5	3	2	0.0	-14.03
c.286G>A	G96S	Likely Benign		Uncertain		1	6-33425894-G-A	5	3.10e-6	-3.049	Likely Benign	0.065	Likely Benign	Likely Benign	0.071	Likely Benign										-0.76	Neutral	0.364	Benign	0.008	Benign	4.25	Benign	0.00	Affected	4.32	1	1	0	-0.4	30.03
c.88C>T	H30Y	Likely Benign		Uncertain		1				-3.047	Likely Benign	0.115	Likely Benign	Likely Benign	0.082	Likely Benign										-1.84	Neutral	0.273	Benign	0.478	Possibly Damaging	3.99	Benign	0.00	Affected	4.32	1	0	2	1.9	26.03
c.3386T>C	L1129P	Likely Benign		Uncertain		2				-2.991	Likely Benign	0.154	Likely Benign	Likely Benign	0.432	Likely Benign										0.27	Neutral	0.971	Probably Damaging	0.773	Possibly Damaging	5.44	Benign	0.00	Affected	4.32	4	-3	-3	-5.4	-16.04
c.3494C>T	S1165L	Likely Benign		Conflicting		2				-2.984	Likely Benign	0.793	Likely Pathogenic	Ambiguous	0.166	Likely Benign										-2.01	Neutral	0.998	Probably Damaging	0.992	Probably Damaging	2.60	Benign	0.33	Tolerated	3.88	3	-3	-2	4.6	26.08																10.1016/j.ajhg.2020.11.011
c.76G>A	G26R	Likely Benign		Benign		1	6-33423485-G-A	3	1.86e-6	-2.946	Likely Benign	0.678	Likely Pathogenic	Likely Benign	0.189	Likely Benign										-2.22	Neutral	0.994	Probably Damaging	0.990	Probably Damaging	3.87	Benign	0.00	Affected	4.32	1	-3	-2	-4.1	99.14
c.3125A>G	Q1042R	Likely Benign		Uncertain		2	6-33443677-A-G	2	1.24e-6	-2.928	Likely Benign	0.413	Ambiguous	Likely Benign	0.300	Likely Benign										-1.39	Neutral	0.586	Possibly Damaging	0.120	Benign	5.48	Benign	0.12	Tolerated	3.77	5	1	1	-1.0	28.06
c.3983G>A	R1328Q	Likely Benign		Uncertain		3	6-33451857-G-A	35	1.49e-4	-2.921	Likely Benign	0.273	Likely Benign	Likely Benign	0.043	Likely Benign										-1.02	Neutral	0.799	Possibly Damaging	0.098	Benign	4.12	Benign	0.03	Affected	3.77	5	1	1	1.0	-28.06
c.2710A>G	M904V	Likely Benign		Likely Benign		2	6-33443262-A-G	77	4.78e-5	-2.907	Likely Benign	0.112	Likely Benign	Likely Benign	0.058	Likely Benign										-0.33	Neutral	0.039	Benign	0.023	Benign	2.80	Benign	0.10	Tolerated	3.77	5	2	1	2.3	-32.06
c.1131G>A	M377I (3D Viewer)	Likely Benign	C2	Uncertain		1	6-33438036-G-A	1	6.23e-7	-2.895	Likely Benign	0.212	Likely Benign	Likely Benign	0.227	Likely Benign	0.76	Ambiguous	0.3	0.54	Ambiguous	0.65	Ambiguous	0.24	Likely Benign	-0.41	Neutral	0.000	Benign	0.001	Benign	5.46	Benign	0.26	Tolerated	4.32	12	1	2	2.6	-18.03
c.323A>G	K108R	Likely Benign		Uncertain		1	6-33432188-A-G	6	3.72e-6	-2.892	Likely Benign	0.148	Likely Benign	Likely Benign	0.184	Likely Benign										0.37	Neutral	0.993	Probably Damaging	0.956	Probably Damaging	4.22	Benign	1.00	Tolerated	3.61	5	3	2	-0.6	28.01
c.4021G>T	A1341S	Likely Benign		Uncertain		1	6-33451895-G-T			-2.867	Likely Benign	0.078	Likely Benign	Likely Benign	0.099	Likely Benign										0.80	Neutral	0.000	Benign	0.001	Benign	4.40	Benign	1.00	Tolerated	3.77	5	1	1	-2.6	16.00
c.2215G>C	E739Q	Likely Benign		Uncertain		1				-2.846	Likely Benign	0.161	Likely Benign	Likely Benign	0.071	Likely Benign										-1.06	Neutral	0.801	Possibly Damaging	0.339	Benign	2.57	Benign	0.00	Affected	4.32	2	2	2	0.0	-0.98
c.196C>G	P66A	Likely Benign		Uncertain		1				-2.845	Likely Benign	0.891	Likely Pathogenic	Ambiguous	0.091	Likely Benign										-1.56	Neutral	0.805	Possibly Damaging	0.539	Possibly Damaging	4.04	Benign	0.00	Affected	4.32	1	1	-1	3.4	-26.04
c.303C>A	H101Q	Likely Benign		Uncertain		1	6-33432168-C-A	1	6.20e-7	-2.827	Likely Benign	0.124	Likely Benign	Likely Benign	0.147	Likely Benign										-0.37	Neutral	0.824	Possibly Damaging	0.880	Possibly Damaging	4.24	Benign	0.00	Affected	4.32	1	3	0	-0.3	-9.01
c.3860C>T	P1287L	Likely Benign		Conflicting		2	6-33447908-C-T			-2.800	Likely Benign	0.117	Likely Benign	Likely Benign	0.061	Likely Benign										-1.66	Neutral	0.021	Benign	0.017	Benign	2.76	Benign	0.02	Affected	3.77	5	-3	-3	5.4	16.04
c.2299A>G	I767V	Likely Benign		Uncertain		1				-2.791	Likely Benign	0.064	Likely Benign	Likely Benign	0.096	Likely Benign										0.10	Neutral	0.072	Benign	0.029	Benign	4.21	Benign	1.00	Tolerated	3.64	6	4	3	-0.3	-14.03
c.2239G>C	V747L	Likely Benign		Uncertain		1	6-33441704-G-C	2	1.24e-6	-2.790	Likely Benign	0.096	Likely Benign	Likely Benign	0.047	Likely Benign										-0.52	Neutral	0.065	Benign	0.033	Benign	2.67	Benign	0.00	Affected	4.32	2	2	1	-0.4	14.03
c.196C>T	P66S	Likely Benign		Benign		1	6-33425804-C-T	2	1.24e-6	-2.760	Likely Benign	0.929	Likely Pathogenic	Ambiguous	0.081	Likely Benign										-1.69	Neutral	0.909	Possibly Damaging	0.641	Possibly Damaging	4.01	Benign	0.00	Affected	4.32	1	1	-1	0.8	-10.04
c.3862A>G	K1288E			Uncertain		1	6-33447910-A-G	5	3.22e-6	-2.751	Likely Benign	0.407	Ambiguous	Likely Benign	0.185	Likely Benign										-3.27	Deleterious	0.979	Probably Damaging	0.973	Probably Damaging	2.13	Pathogenic	0.00	Affected	3.77	5	1	0	0.4	0.94
c.2924C>G	T975S	Likely Benign		Uncertain		1				-2.743	Likely Benign	0.068	Likely Benign	Likely Benign	0.109	Likely Benign										-0.57	Neutral	0.059	Benign	0.061	Benign	4.16	Benign	0.20	Tolerated			1	1	-0.1	-14.03
c.2711T>C	M904T	Likely Benign		Uncertain		1				-2.721	Likely Benign	0.668	Likely Pathogenic	Likely Benign	0.042	Likely Benign										-1.15	Neutral	0.277	Benign	0.103	Benign	2.78	Benign	0.18	Tolerated	3.77	5	-1	-1	-2.6	-30.09
c.3424T>C	S1142P	Likely Benign		Likely Benign		1	6-33444459-T-C	1	6.20e-7	-2.713	Likely Benign	0.222	Likely Benign	Likely Benign	0.107	Likely Benign										-2.19	Neutral	0.918	Possibly Damaging	0.761	Possibly Damaging	2.64	Benign	0.00	Affected	4.32	4	-1	1	-0.8	10.04
c.1913A>G	K638R (3D Viewer)	Likely Benign	GAP	Uncertain		1				-2.700	Likely Benign	0.110	Likely Benign	Likely Benign	0.216	Likely Benign	0.09	Likely Benign	0.1	-0.04	Likely Benign	0.03	Likely Benign	0.53	Ambiguous	-2.55	Deleterious	0.649	Possibly Damaging	0.240	Benign	3.41	Benign	0.13	Tolerated	3.37	31	2	3	-0.6	28.01
c.3913A>G	T1305A	Likely Benign		Conflicting		4	6-33451787-A-G	30	1.86e-5	-2.692	Likely Benign	0.055	Likely Benign	Likely Benign	0.069	Likely Benign										1.74	Neutral	0.000	Benign	0.001	Benign	3.24	Benign	1.00	Tolerated	3.77	5	1	0	2.5	-30.03
c.277C>G	R93G	Likely Benign		Uncertain		1				-2.674	Likely Benign	0.400	Ambiguous	Likely Benign	0.093	Likely Benign										-1.69	Neutral	0.103	Benign	0.019	Benign	3.99	Benign	0.00	Affected	4.32	1	-2	-3	4.1	-99.14
c.3344T>C	I1115T	Likely Benign		Benign		9	6-33443896-T-C	20536	1.36e-2	-2.670	Likely Benign	0.068	Likely Benign	Likely Benign	0.100	Likely Benign										-0.04	Neutral	0.000	Benign	0.001	Benign	2.76	Benign	0.23	Tolerated	4.32	2	0	-1	-5.2	-12.05
c.3354C>A	S1118R	Likely Benign		Uncertain		1				-2.670	Likely Benign	0.553	Ambiguous	Likely Benign	0.166	Likely Benign										-0.74	Neutral	0.034	Benign	0.023	Benign	5.17	Benign	0.05	Affected	4.32	2	-1	0	-3.7	69.11
c.53A>G	Y18C	Likely Benign		Uncertain		1	6-33420317-A-G	44	2.88e-5	-2.658	Likely Benign	0.251	Likely Benign	Likely Benign	0.102	Likely Benign										-0.56	Neutral	0.872	Possibly Damaging	0.206	Benign	4.04	Benign	0.00	Affected	4.32	1	0	-2	3.8	-60.04
c.603T>A	D201E (3D Viewer)	Likely Benign	PH	Benign		1				-2.640	Likely Benign	0.406	Ambiguous	Likely Benign	0.165	Likely Benign	0.42	Likely Benign	0.2	1.99	Ambiguous	1.21	Ambiguous	0.23	Likely Benign	-0.69	Neutral	0.633	Possibly Damaging	0.108	Benign	4.30	Benign	1.00	Tolerated	3.46	9	3	2	0.0	14.03	258.7	-24.8	0.9	0.1	-0.3	0.2						X		Uncertain	Asp201, an acidic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another acidic residue, glutamate. The carboxylate groups of both Asp201 and Glu201 side chains form hydrogen bonds with the hydroxyl group of Ser221 in the simulations. Due to its shorter side chain, Asp201 can also hydrogen bond with the backbone amide groups of neighboring loop residues Ser204 and Asp203. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations.
c.603T>G	D201E (3D Viewer)	Likely Benign	PH	Conflicting		2	6-33435245-T-G	20	1.24e-5	-2.640	Likely Benign	0.406	Ambiguous	Likely Benign	0.165	Likely Benign	0.42	Likely Benign	0.2	1.99	Ambiguous	1.21	Ambiguous	0.23	Likely Benign	-0.69	Neutral	0.633	Possibly Damaging	0.108	Benign	4.30	Benign	1.00	Tolerated	3.46	9	3	2	0.0	14.03	258.7	-24.8	0.9	0.1	-0.3	0.2						X		Uncertain	Asp201, an acidic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another acidic residue, glutamate. The carboxylate groups of both Asp201 and Glu201 side chains form hydrogen bonds with the hydroxyl group of Ser221 in the simulations. Due to its shorter side chain, Asp201 can also hydrogen bond with the backbone amide groups of neighboring loop residues Ser204 and Asp203. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations.
c.2270G>C	G757A	Likely Benign		Uncertain		1				-2.626	Likely Benign	0.091	Likely Benign	Likely Benign	0.066	Likely Benign										-0.45	Neutral	0.267	Benign	0.127	Benign	2.73	Benign	0.35	Tolerated			1	0	2.2	14.03
c.68A>G	D23G	Likely Benign		Uncertain		1				-2.622	Likely Benign	0.684	Likely Pathogenic	Likely Benign	0.100	Likely Benign										-2.45	Neutral	0.805	Possibly Damaging	0.539	Possibly Damaging	3.50	Benign	0.00	Affected			1	-1	3.1	-58.04
c.2249G>A	G750E			Uncertain		1				-2.618	Likely Benign	0.413	Ambiguous	Likely Benign	0.146	Likely Benign										-2.27	Neutral	1.000	Probably Damaging	0.982	Probably Damaging	2.49	Pathogenic	0.01	Affected	3.99	5	0	-2	-3.1	72.06
c.2168C>T	T723I (3D Viewer)	Likely Benign	GAP	Likely Benign		1	6-33441633-C-T	2	1.24e-6	-2.591	Likely Benign	0.120	Likely Benign	Likely Benign	0.045	Likely Benign	-0.39	Likely Benign	0.0	-0.20	Likely Benign	-0.30	Likely Benign	0.26	Likely Benign	-2.09	Neutral	0.088	Benign	0.030	Benign	3.39	Benign	0.03	Affected	3.50	8	0	-1	5.2	12.05	252.3	-31.6	0.0	0.0	-0.2	0.2						X		Uncertain	The hydroxyl group of Thr723, located on the outer surface of an α-helix (res. Leu714-Arg726), continuously forms hydrogen bonds with the backbone carbonyl of Asn719 in the WT simulations, potentially lowering the stability of the α-helix. In the variant simulations, the sec-butyl side chain of Ile723 cannot form any hydrogen bonds, which, in theory, could increase the helix stability. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations.
c.2863T>C	S955P	Likely Benign		Uncertain		1	6-33443415-T-C	3	1.86e-6	-2.584	Likely Benign	0.073	Likely Benign	Likely Benign	0.098	Likely Benign										-0.75	Neutral	0.001	Benign	0.004	Benign	2.33	Pathogenic	0.00	Affected	3.77	5	1	-1	-0.8	10.04
c.2695A>G	I899V	Likely Benign		Benign		1	6-33443247-A-G	6	3.72e-6	-2.569	Likely Benign	0.074	Likely Benign	Likely Benign	0.040	Likely Benign										0.09	Neutral	0.220	Benign	0.078	Benign	2.75	Benign	0.92	Tolerated	4.32	4	4	3	-0.3	-14.03
c.249A>T	R83S	Likely Benign		Uncertain		1				-2.550	Likely Benign	0.999	Likely Pathogenic	Likely Pathogenic	0.094	Likely Benign										-1.87	Neutral	0.909	Possibly Damaging	0.587	Possibly Damaging	3.19	Benign	0.00	Affected	4.32	1	0	-1	3.7	-69.11
c.37A>G	I13V	Likely Benign		Uncertain		1				-2.497	Likely Benign	0.105	Likely Benign	Likely Benign	0.110	Likely Benign										0.01	Neutral	0.000	Benign	0.000	Benign	4.25	Benign	0.00	Affected			4	3	-0.3	-14.03
c.2343G>A	M781I	Likely Benign		Benign		1				-2.484	Likely Benign	0.323	Likely Benign	Likely Benign	0.101	Likely Benign										0.05	Neutral	0.000	Benign	0.001	Benign	2.89	Benign	1.00	Tolerated	3.64	6	1	2	2.6	-18.03
c.113C>T	P38L	Likely Benign		Conflicting		4	6-33423522-C-T	8	4.96e-6	-2.469	Likely Benign	0.197	Likely Benign	Likely Benign	0.141	Likely Benign										-2.56	Deleterious	0.983	Probably Damaging	0.931	Probably Damaging	4.02	Benign	0.00	Affected	4.32	1	-3	-3	5.4	16.04
c.3116T>C	I1039T	Likely Benign		Uncertain		1	6-33443668-T-C	12	7.43e-6	-2.465	Likely Benign	0.645	Likely Pathogenic	Likely Benign	0.193	Likely Benign										0.45	Neutral	0.004	Benign	0.008	Benign	2.75	Benign	0.10	Tolerated	3.77	5	-1	0	-5.2	-12.05
c.335G>C	G112A	Likely Benign		Uncertain		1	6-33432200-G-C	15	9.30e-6	-2.456	Likely Benign	0.119	Likely Benign	Likely Benign	0.114	Likely Benign										-2.34	Neutral	0.231	Benign	0.054	Benign	4.07	Benign	0.00	Affected	3.61	5	1	0	2.2	14.03
c.3305C>T	A1102V	Likely Benign		Benign		1	6-33443857-C-T			-2.440	Likely Benign	0.077	Likely Benign	Likely Benign	0.081	Likely Benign										-1.27	Neutral	0.017	Benign	0.028	Benign	2.29	Pathogenic	0.12	Tolerated	3.77	5	0	0	2.4	28.05
c.3307C>T	R1103C			Uncertain		1	6-33443859-C-T	6	3.92e-6	-2.440	Likely Benign	0.246	Likely Benign	Likely Benign	0.140	Likely Benign										-3.01	Deleterious	0.996	Probably Damaging	0.787	Possibly Damaging	2.41	Pathogenic	0.01	Affected	3.77	5	-3	-4	7.0	-53.05
c.2928T>G	F976L	Likely Benign		Uncertain		1				-2.432	Likely Benign	0.825	Likely Pathogenic	Ambiguous	0.212	Likely Benign										-0.87	Neutral	0.264	Benign	0.102	Benign	4.20	Benign	0.53	Tolerated	4.32	2	2	0	1.0	-34.02
c.2275A>C	M759L	Likely Benign		Uncertain		1	6-33441740-A-C	2	1.24e-6	-2.431	Likely Benign	0.093	Likely Benign	Likely Benign	0.048	Likely Benign										-0.53	Neutral	0.002	Benign	0.005	Benign	2.84	Benign	1.00	Tolerated	3.99	5	4	2	1.9	-18.03
c.2210A>C	Q737P	Likely Benign		Uncertain		1				-2.407	Likely Benign	0.054	Likely Benign	Likely Benign	0.154	Likely Benign										-1.22	Neutral	0.005	Benign	0.013	Benign	2.78	Benign	0.04	Affected	4.07	3	-1	0	1.9	-31.01
c.1918A>T	T640S (3D Viewer)	Likely Benign	GAP	Benign		1	6-33441177-A-T	1	6.20e-7	-2.371	Likely Benign	0.062	Likely Benign	Likely Benign	0.088	Likely Benign	-0.78	Ambiguous	0.1	0.43	Likely Benign	-0.18	Likely Benign	-0.30	Likely Benign	0.92	Neutral	0.000	Benign	0.001	Benign	3.60	Benign	0.33	Tolerated	3.37	30	1	1	-0.1	-14.03
c.2935T>C	F979L	Likely Benign		Uncertain		1				-2.341	Likely Benign	0.870	Likely Pathogenic	Ambiguous	0.228	Likely Benign										-1.00	Neutral	0.625	Possibly Damaging	0.430	Benign	4.22	Benign	0.73	Tolerated	4.32	2	2	0	1.0	-34.02
c.3308G>T	R1103L	Likely Benign		Uncertain		1	6-33443860-G-T			-2.330	Likely Benign	0.205	Likely Benign	Likely Benign	0.173	Likely Benign										-2.35	Neutral	0.002	Benign	0.005	Benign	2.44	Pathogenic	0.02	Affected	3.77	5	-3	-2	8.3	-43.03
c.3310C>T	P1104S	Likely Benign		Benign		1	6-33443862-C-T	1	6.54e-7	-2.330	Likely Benign	0.073	Likely Benign	Likely Benign	0.088	Likely Benign										-0.30	Neutral	0.770	Possibly Damaging	0.404	Benign	2.77	Benign	0.10	Tolerated	3.77	5	-1	1	0.8	-10.04
c.2408A>G	K803R	Likely Benign	SH3-binding motif	Uncertain		1				-2.281	Likely Benign	0.097	Likely Benign	Likely Benign	0.018	Likely Benign										-1.52	Neutral	0.103	Benign	0.038	Benign	2.38	Pathogenic	0.00	Affected	3.77	5	3	2	-0.6	28.01
c.3907G>A	G1303S	Likely Benign		Uncertain		1				-2.271	Likely Benign	0.125	Likely Benign	Likely Benign	0.155	Likely Benign										-0.19	Neutral	0.649	Possibly Damaging	0.433	Benign	2.84	Benign	0.18	Tolerated			1	0	-0.4	30.03
c.172A>G	M58V	Likely Benign		Uncertain		1				-2.211	Likely Benign	0.688	Likely Pathogenic	Likely Benign	0.160	Likely Benign										-0.71	Neutral	0.006	Benign	0.091	Benign	4.19	Benign	0.00	Affected	4.32	1	1	2	2.3	-32.06
c.48G>A	M16I	Likely Benign		Uncertain		1	6-33420312-G-A	1	6.49e-7	-2.198	Likely Benign	0.722	Likely Pathogenic	Likely Benign	0.057	Likely Benign										-0.15	Neutral	0.000	Benign	0.000	Benign	4.28	Benign	0.00	Affected	4.32	1	2	1	2.6	-18.03
c.86T>C	M29T	Likely Benign		Uncertain		1				-2.167	Likely Benign	0.122	Likely Benign	Likely Benign	0.199	Likely Benign										-0.37	Neutral	0.018	Benign	0.184	Benign	4.33	Benign	0.00	Affected	4.32	1	-1	-1	-2.6	-30.09
c.2632A>G	T878A	Likely Benign		Uncertain		1				-2.154	Likely Benign	0.081	Likely Benign	Likely Benign	0.088	Likely Benign										-0.67	Neutral	0.003	Benign	0.006	Benign	2.73	Benign	0.18	Tolerated	3.77	5	1	0	2.5	-30.03
c.1594A>C	T532P (3D Viewer)	Likely Benign	GAP	Benign		1				-2.143	Likely Benign	0.061	Likely Benign	Likely Benign	0.201	Likely Benign	-0.30	Likely Benign	0.2	0.06	Likely Benign	-0.12	Likely Benign	0.08	Likely Benign	-0.90	Neutral	0.005	Benign	0.008	Benign	-1.28	Pathogenic	0.18	Tolerated	3.37	35	0	-1	-0.9	-3.99	174.2	35.1	0.4	0.0	0.1	0.0						X		Potentially Benign	Thr532 is located on an α-α loop between the two α-helices (res. Gly502-Tyr518 and Ala533-Val560) facing the membrane. In the WT simulations, the hydroxyl group of Thr532 occasionally forms hydrogen bonds with the backbone atoms of other loop residues without any specific interaction. In the variant simulations, the Pro532 residue swap does not cause structural changes. Although hydrophilic residues seem more favorable in the loop, the pyrrolidine side chain of proline is well suited for unstructured protein regions such as loops. However, due to its location at the SynGAP-membrane interface, the effect of the residue swap cannot be fully addressed using the SynGAP solvent-only simulations.
c.3484C>T	P1162S	Likely Benign		Uncertain		1				-2.118	Likely Benign	0.913	Likely Pathogenic	Ambiguous	0.215	Likely Benign										-1.93	Neutral	1.000	Probably Damaging	0.999	Probably Damaging	2.73	Benign	0.55	Tolerated	3.88	3	1	-1	0.8	-10.04
c.3487C>G	H1163D			Uncertain		1				-2.107	Likely Benign	0.949	Likely Pathogenic	Ambiguous	0.476	Likely Benign										-2.60	Deleterious	0.991	Probably Damaging	0.991	Probably Damaging	5.44	Benign	0.31	Tolerated	3.88	3	1	-1	-0.3	-22.05
c.2567A>G	N856S	Likely Benign		Uncertain		1	6-33443119-A-G	2	1.24e-6	-2.104	Likely Benign	0.064	Likely Benign	Likely Benign	0.040	Likely Benign										-1.54	Neutral	0.901	Possibly Damaging	0.535	Possibly Damaging	4.16	Benign	0.30	Tolerated	3.88	3	1	1	2.7	-27.03
c.3631A>G	M1211V	Likely Benign	Coiled-coil	Benign		1	6-33446623-A-G	3	1.86e-6	-2.101	Likely Benign	0.258	Likely Benign	Likely Benign	0.412	Likely Benign										-0.29	Neutral	0.932	Possibly Damaging	0.949	Probably Damaging	5.43	Benign	0.72	Tolerated	3.77	5	1	2	2.3	-32.06
c.3410A>C	H1137P	Likely Benign		Benign		1	6-33444445-A-C	12	7.44e-6	-2.098	Likely Benign	0.054	Likely Benign	Likely Benign	0.419	Likely Benign										-1.93	Neutral	0.925	Possibly Damaging	0.703	Possibly Damaging	5.29	Benign	0.00	Affected	4.32	4	-2	0	1.6	-40.02
c.3049T>C	F1017L	Likely Benign		Benign		1				-2.048	Likely Benign	0.934	Likely Pathogenic	Ambiguous	0.157	Likely Benign										-2.38	Neutral	0.798	Possibly Damaging	0.373	Benign	2.65	Benign	0.72	Tolerated	3.77	5	0	2	1.0	-34.02
c.194A>G	H65R	Likely Benign		Uncertain		1	6-33425802-A-G	1	6.20e-7	-1.980	Likely Benign	0.967	Likely Pathogenic	Likely Pathogenic	0.073	Likely Benign										-1.60	Neutral	0.462	Possibly Damaging	0.227	Benign	4.19	Benign	0.00	Affected	4.32	1	2	0	-1.3	19.05
c.2669G>C	R890P	Likely Benign		Likely Benign		2	6-33443221-G-C	28	1.74e-5	-1.931	Likely Benign	0.301	Likely Benign	Likely Benign	0.191	Likely Benign										-1.21	Neutral	0.999	Probably Damaging	0.977	Probably Damaging	4.02	Benign	0.28	Tolerated	4.32	4	0	-2	2.9	-59.07
c.3092T>C	M1031T	Likely Benign		Uncertain		1	6-33443644-T-C	2	1.24e-6	-1.863	Likely Benign	0.540	Ambiguous	Likely Benign	0.085	Likely Benign										-0.24	Neutral	0.002	Benign	0.005	Benign	2.67	Benign	1.00	Tolerated	3.77	5	-1	-1	-2.6	-30.09
c.3932T>C	L1311P	Likely Benign		Likely Benign		1	6-33451806-T-C	1	6.21e-7	-1.831	Likely Benign	0.079	Likely Benign	Likely Benign	0.123	Likely Benign										-0.52	Neutral	0.579	Possibly Damaging	0.335	Benign	2.72	Benign	0.18	Tolerated	3.77	5	-3	-3	-5.4	-16.04
c.819G>T	E273D (3D Viewer)	Likely Benign	C2	Benign		1	6-33437724-G-T	2	1.24e-6	-1.811	Likely Benign	0.058	Likely Benign	Likely Benign	0.092	Likely Benign	0.26	Likely Benign	0.1	-0.48	Likely Benign	-0.11	Likely Benign	-0.63	Ambiguous	1.99	Neutral	0.004	Benign	0.010	Benign	2.00	Pathogenic	1.00	Tolerated	3.38	18	3	2	0.0	-14.03	223.1	22.1	0.2	0.0	0.0	0.1						X		Potentially Benign	The negatively charged residue Glu273, located in a β hairpin loop (res. Glu273-Lys278) that connects two anti-parallel β sheet strands, is replaced with another negatively charged residue, aspartate. Because the C2 domain loop faces the membrane surface, the potentially crucial role of the carboxylate group of Glu273 or Asp273 on SynGAP-membrane association cannot be fully explored via solvent-only simulations.As a minor note, the neighboring residue Arg272, which stacks with the indole ring of the Trp362 side chain and directly faces RasGTPase, forms a salt bridge more often with Asp273 than with the non-mutated Glu273 in the simulations. Regardless, due to the similar physicochemical properties of the WT and variant residues at the membrane interface, the residue swap is likely to be well tolerated.
c.3442A>T	M1148L	Likely Benign		Uncertain		1				-1.777	Likely Benign	0.093	Likely Benign	Likely Benign	0.068	Likely Benign										-1.13	Neutral	0.016	Benign	0.016	Benign	2.62	Benign	0.00	Affected	4.32	2	4	2	1.9	-18.03
c.380G>A	R127Q	Likely Benign		Uncertain		1	6-33432245-G-A	6	3.72e-6	-1.711	Likely Benign	0.320	Likely Benign	Likely Benign	0.037	Likely Benign										-1.04	Neutral	0.006	Benign	0.001	Benign	4.04	Benign	0.02	Affected	3.74	4	1	1	1.0	-28.06
c.2186A>G	N729S (3D Viewer)	Likely Benign	GAP	Uncertain		1				-1.578	Likely Benign	0.066	Likely Benign	Likely Benign	0.063	Likely Benign	0.14	Likely Benign	0.1	1.34	Ambiguous	0.74	Ambiguous	-0.36	Likely Benign	-0.42	Neutral	0.221	Benign	0.027	Benign	3.38	Benign	0.93	Tolerated	3.59	7	1	1	2.7	-27.03
c.3633G>A	M1211I	Likely Benign	Coiled-coil	Uncertain		1	6-33446625-G-A	3	1.86e-6	-1.537	Likely Benign	0.764	Likely Pathogenic	Likely Benign	0.298	Likely Benign										-0.42	Neutral	0.969	Probably Damaging	0.968	Probably Damaging	5.40	Benign	1.00	Tolerated	3.77	5	1	2	2.6	-18.03
c.3394T>C	S1132P	Likely Benign		Conflicting		3	6-33443946-T-C	1	6.74e-7	-1.423	Likely Benign	0.144	Likely Benign	Likely Benign	0.301	Likely Benign										0.38	Neutral	0.003	Benign	0.006	Benign	5.40	Benign	0.28	Tolerated	4.32	4	1	-1	-0.8	10.04
c.1851G>T	E617D (3D Viewer)	Likely Benign	GAP	Uncertain		1				-1.349	Likely Benign	0.241	Likely Benign	Likely Benign	0.322	Likely Benign	0.12	Likely Benign	0.1	0.80	Ambiguous	0.46	Likely Benign	0.07	Likely Benign	-0.01	Neutral	0.994	Probably Damaging	0.979	Probably Damaging	-1.35	Pathogenic	0.88	Tolerated	3.37	35	2	3	0.0	-14.03
c.3361A>G	S1121G	Likely Benign		Uncertain		1	6-33443913-A-G	1	7.00e-7	-1.220	Likely Benign	0.054	Likely Benign	Likely Benign	0.067	Likely Benign										-0.53	Neutral	0.003	Benign	0.004	Benign	6.63	Benign	0.00	Affected	3.77	5	0	1	0.4	-30.03
c.3983G>C	R1328P	Likely Benign		Benign		1	6-33451857-G-C			-1.220	Likely Benign	0.466	Ambiguous	Likely Benign	0.060	Likely Benign										-2.01	Neutral	0.927	Possibly Damaging	0.452	Possibly Damaging	4.06	Benign	0.01	Affected	3.77	5	0	-2	2.9	-59.07
c.3964G>C	A1322P	Likely Benign		Benign		1	6-33451838-G-C			-1.153	Likely Benign	0.063	Likely Benign	Likely Benign	0.090	Likely Benign										0.03	Neutral	0.000	Benign	0.000	Benign	4.15	Benign	0.23	Tolerated	3.77	5	1	-1	-3.4	26.04
c.3572G>A	R1191Q	Likely Benign	Coiled-coil	Uncertain		2	6-33444607-G-A	9	5.58e-6	-1.069	Likely Benign	0.943	Likely Pathogenic	Ambiguous	0.343	Likely Benign										-1.41	Neutral	0.998	Probably Damaging	0.992	Probably Damaging	2.68	Benign	0.08	Tolerated	3.82	4	1	1	1.0	-28.06
c.1198G>C	V400L (3D Viewer)	Likely Benign	C2	Benign		1	6-33438103-G-C	22	1.36e-5	-1.000	Likely Benign	0.137	Likely Benign	Likely Benign	0.325	Likely Benign	-0.71	Ambiguous	0.2	0.39	Likely Benign	-0.16	Likely Benign	-0.29	Likely Benign	-0.60	Neutral	0.001	Benign	0.001	Benign	5.33	Benign	0.64	Tolerated	3.38	27	2	1	-0.4	14.03	251.0	-30.1	0.0	0.0	0.7	0.1						X		Potentially Benign	The iso-propyl side chain of Val400, located in an anti-parallel β sheet strand (res. Ala399-Ile411), hydrophobically packs against hydrophobic residues within the anti-parallel β sheet of the C2 domain (e.g., Ile268, Ala404, Leu325, Leu402). Val400 is swapped for another hydrophobic residue, leucine, whose branched hydrocarbon side chain is of a comparable size and thus packs favorably within the C2 domain. In short, the residue swap has no apparent negative effect on the structure based on the variant simulations.	10.1016/j.ajhg.2020.11.011
c.3434A>G	N1145S	Likely Benign		Uncertain		1	6-33444469-A-G	2	1.24e-6	-0.989	Likely Benign	0.126	Likely Benign	Likely Benign	0.308	Likely Benign										-1.15	Neutral	0.997	Probably Damaging	0.989	Probably Damaging	5.55	Benign	0.89	Tolerated	4.32	4	1	1	2.7	-27.03
c.458C>A	T153N	Likely Benign		Conflicting		3				-0.739	Likely Benign	0.226	Likely Benign	Likely Benign	0.161	Likely Benign										0.88	Neutral	0.888	Possibly Damaging	0.537	Possibly Damaging	4.23	Benign	0.81	Tolerated	3.61	5	0	0	-2.8	13.00
c.2768T>A	I923N	Likely Benign		Uncertain		1				-0.733	Likely Benign	0.712	Likely Pathogenic	Likely Benign	0.108	Likely Benign										-1.16	Neutral	0.991	Probably Damaging	0.793	Possibly Damaging	2.70	Benign	0.13	Tolerated	3.77	5	-2	-3	-8.0	0.94
c.2809G>C	D937H	Likely Benign		Uncertain		1				-0.733	Likely Benign	0.677	Likely Pathogenic	Likely Benign	0.150	Likely Benign										-1.74	Neutral	1.000	Probably Damaging	0.975	Probably Damaging	2.68	Benign	0.13	Tolerated	3.77	5	-1	1	0.3	22.05
c.1586T>C	I529T (3D Viewer)	Likely Benign	GAP	Uncertain		1				-0.539	Likely Benign	0.336	Likely Benign	Likely Benign	0.343	Likely Benign	0.22	Likely Benign	0.2	0.16	Likely Benign	0.19	Likely Benign	0.17	Likely Benign	0.24	Neutral	0.872	Possibly Damaging	0.820	Possibly Damaging	-1.23	Pathogenic	0.55	Tolerated	3.37	35	0	-1	-5.2	-12.05	207.2	29.8	0.2	0.0	0.2	0.1						X		Potentially Benign	Ile529 is located on an α-α loop between the two α-helices (res. Gly502-Tyr518 and Ala533-Val560). In the WT simulations, the sec-butyl side chain of Ile529 faces the membrane interface and shows no specific interactions. In the variant simulations, the hydroxyl group of Thr529 forms a hydrogen bond with the carboxylate side chain of Asp527, but no negative structural changes are observed. However, due to its location near the SynGAP-membrane interface, the effect of the residue swap cannot be fully addressed using the SynGAP solvent-only simulations.
c.2909A>G	E970G	Likely Benign		Benign		1				-0.167	Likely Benign	0.139	Likely Benign	Likely Benign	0.139	Likely Benign										-0.93	Neutral	0.144	Benign	0.058	Benign	4.09	Benign	0.10	Tolerated	4.32	2	0	-2	3.1	-72.06
c.2914C>G	P972A	Likely Benign		Uncertain		1	6-33443466-C-G	1	6.20e-7	-0.167	Likely Benign	0.045	Likely Benign	Likely Benign	0.046	Likely Benign										-0.89	Neutral	0.016	Benign	0.011	Benign	4.29	Benign	0.07	Tolerated	4.32	2	-1	1	3.4	-26.04
c.3943T>C	W1315R	Likely Benign		Uncertain		1				0.205	Likely Benign	0.660	Likely Pathogenic	Likely Benign	0.114	Likely Benign										1.31	Neutral	0.000	Benign	0.001	Benign	4.37	Benign	0.91	Tolerated	3.77	5	2	-3	-3.6	-30.03